May-Hegglin Anomaly Research Articles

May–Hegglin anomaly in a dog

An 8-year-old female spayed Pug dog was presented for evaluation of cutaneous lesions occurring secondary to immunosuppressive treatment of presumed immune-mediated thrombocytopenia. Abnormal hematologic findings included persistent thrombocytopenia, macrothrombocytes, and variably shaped, often fusiform, blue cytoplasmic inclusions in neutrophils. May-Hegglin anomaly (MHA) was suspected based on the morphologic appearance of platelets and neutrophils. Examination of cells by transmission electron microscopy revealed normal platelet ultrastructure; neutrophil inclusions had features similar to those reported for inclusions in human MHA. Neutrophil function was within normal limits based on flow cytometric analysis. Thrombelastography indicated a prolonged clotting time (r), and PlateletMapping showed a lack of response to 2 μM ADP compared with a moderate response in the control dog. Immunocytochemical staining of blood smears using 2 commercially available antibodies against MYH9 protein (nonmuscle myosin heavy chain II) yielded negative results. However, genomic DNA sequencing analysis of the dog's MYH9 gene identified a single point mutation, resulting in substitution of lysine for glutamine at the 1841 amino acid position; this mutation is identical to one identified in people with MHA. To our knowledge, this is the first report of an MYH9 mutation in the dog. MHA-associated macrothrombocytopenia may be mistaken for immune-mediated thrombocytopenia.

A notable case report of May-Hegglin anomaly with immune complex-related nephropathy: a genetic and histological analysis

May-Hegglin anomaly (MHA) is a rare autosomal dominant disease characterized by macrothrombocytopenia and leukocyte inclusions with microfilaments in the ribosomes. Mutations in the MYH9 gene, encoding non-muscle myosin heavy chain IIA (NMMHC-IIA) have been identified in patients with MHA and other MYH9-related diseases. Two young males (an older and younger brother) presented with macrothrombocytopenia and leukocyte inclusion bodies. Electron microscopy (EM) revealed parallel filaments in leukocyte inclusion bodies characteristic of MHA. Immunofluorescence microscopy (IF) showed NMMHC-IIA antibodies in 1 - 2 leukocyte inclusion bodies. These findings were consistent with MHA and they were identified to express the MYH9 mutation, D1424H. The older brother underwent a renal biopsy because of persistent proteinuria. Histology revealed mesangial proliferative glomerulonephritis with granular deposits of IgG and C1q. EM showed that the dense deposits were located in subendothelial cells, mesangial cells and Bowman's capsule. Immunocytochemistry revealed that NMMHC-IIA antibodies were localized in podocyte and endothelial cells in the glomerulus. Moreover, the expression of nephrin and podocin, slit diagram protein, was normal. An inflammatory mechanism may occur separately from MYH9-related disease. This report presents a case of MHA with immune complex-related nephropathy.

The first report of homozygous May-Hegglin anomaly E1841K mutation

The first report of homozygous May-Hegglin anomaly E1841K mutation

The start of hemodialysis in a patient with May-Hegglin anomaly complicated by Alport-like symptoms

May-Hegglin anomaly（MHA）は血小板減少，巨大血小板，顆粒球封入体を三徴とする，まれな常染色体優性遺伝性疾患であり，原因として非筋肉性A型ミオシン重鎖（myosin IIA）をコードする遺伝子である，MYH9の異常が指摘されている．さらにMYH9の異常がAlport症状（感音性難聴，白内障，腎炎）の発現に重要な役割を担っているものと考えられている．症例は45歳，女性．2007年6月より全身倦怠感，頻回の嘔吐を主訴として入院となった．胃内視鏡検査では潰瘍の所見はなくマロリーワイス症候群と診断され止血処置が施行された．末梢血のMay-Giemsa染色では血小板減少，巨大血小板，顆粒球封入体を認めた．血液生化学では著明なクレアチニンの上昇を認め血液透析治療を開始した．子供は4歳時にMHAと診断されたが遺伝子診断はされていない．父親は血液透析治療を受けていたが46歳で亡くなっていた．聴力検査では両側で高音領域の感音性難聴を認め眼科受診では両側の白内障が観察された．遺伝子検査ではMYH9のエクソン38領域を増幅し，その塩基配列を解析したところヘテロ接合性のE1841Kの変異を認めた．また顆粒球の免疫蛍光染色では細胞質にmyosin IIAが紡錘状に異常集積していた．以上のデータより本症例をAlport症状を伴ったMHAと診断した．

Myh9Q1443L Is a Novel Mouse Model of MYH9-Related Disorders

AbstractAbstract 2527May-Hegglin Anomaly was originally defined as patients with macrothrombocytopenia. It is now recognized that the phenotypes of May-Hegglin Anomaly and the related syndromes described by Epstein, Fechtner and Sebastian overlap comprising macrothrombocytopenia, neutrophil inclusions, deafness, cataract formation and nephritis. These disorders are defined by mutations in the non-muscle myosin heavy chain IIA gene, MYH9 and have been termed MYH9-Related Disorders.Myh9 is required during murine embryogenesis as Myh9-null embryos die of patterning defects. Megakaryocyte-specific deletion of Myh9 has been performed by the Gachet group and Shivdasani and colleagues examined megakaryocyte function in Myh9-deficient embryonic stem cells induced to differentiate in vitro. The phenotypes of these mice include increased bleeding times, absence of clot retraction and defective Integrin β3 phosphorylation coupling to impaired activation of downstream Rho-Rock signalling and lamellipodia formation. To date, no knock-in MYH9 alleles corresponding to MYH9-related Disorder mutations have been reported. MYH9-related Disorders frequently are misdiagnosed as Chronic Immune Thrombocytopenia, so having enhanced knowledge of the molecular etiology of mutant MYH9 alleles is a priority.Our group has been interested in utilizing random mutagenesis to identify novel alleles of human hematopoietic disorders. We performed a dominant screen in which 129 male mice were mutagenized with ENU and back-crossing was performed on the C57BL/6 background. We identified a heritable line (7238) with macrothrombocytopenia that mapped to a 4.25 Mb region on mouse Chromosome 15. Due to our inability to further refine the interval through back-crossing, we performed high throughput sequencing by comparing SNPs between 129, C57BL/6, 7238/+ and 7238/7238 mice. We identified 18 novel variations, including 1 that corresponded to a coding change - Myh9 Q1443L. Subsequent Sanger sequencing and back-crossing eliminated the remaining 17 variations, confirming our assignment of the 7238 phenotype to a mutation of Myh9. The Myh9 Q1443L allele is within proximity of the MYH9 D1424Y/N/H mutations found within clinical specimens.Myh9Q1443L/Q1443L mice are viable allowing us to examine the effect of mutation of one or both alleles of Myh9. Myh9Q1443L/Q1443L mice had increased bleeding times, whereas Myh9Q1443L/+ mice were identical to wild type mice. Platelet aggregation experiments were performed after ADP or thrombin stimulation. Decreased aggregation was observed in a dosage-dependent manner, with Myh9Q1443L/+ mice displaying intermediate levels when compared with Myh9Q1443L/Q1443L co-hort. Adherence and aggregation of Myh9Q1443L/Q1443L platelets to a collagen matrix was decreased at shear rates of 350/s and 1800/s. Staining of Myh9Q1443L/+ and Myh9Q1443L/Q1443L neutrophils also revealed neutrophil inclusions.In addition to the hematopoietic phenotypes, we have observed increased cataract formation with a frequency of 36% in wild type animals, 60% in Myh9Q1443L/+ and 92% in Myh9Q1443L/Q1443L mice. Sporadic hematuria and proteinuria is found in Myh9Q1443L mice. We are currently performing albumen loading and lipopolysaccharide activation experiments to determine whether 7238 mice have altered response to nephric stress. We are crossing 7238 mice to the DBA genetic background, which is more sensitive to subtle kidney phenotypes. We performed auditory brain response measurements on aged wild type, Myh9Q1443L/+ and Myh9Q1443L/Q1443L mice and observed no differences in frequency responses ranging from 2 to 24kHz. Myh9Q1443L/+ mice displayed hypertrophy of the preputial gland whereas Myh9Q1443L/Q1443L males showed atrophy of this gland and Myh9Q1443L/Q1443L male mice have reduced fertility. No differences in fertility have been described to date in MYH9 related disorders.In conclusion, Myh9Q1443L/Q1443L mice display macrothrombocytopenia, neutrophil inclusions and cataract formation described in MYH9-related disorders and represent the first animal model of May-Hegglin Anomaly. Disclosures:No relevant conflicts of interest to declare.

Glomerular pathology in autosomal dominant MYH9 spectrum disorders: what are the clues telling us about disease mechanism?

Genetic variation in MYH9, encoding non-muscle heavy chain IIA, has been recognized for over a decade as the cause of an autosomal dominant syndrome characterized by macrothrombocytopenia, neutrophil inclusions, and glomerular pathology. More recently, genetic variation in the MYH9 region on chromosome 22 has been associated with chronic kidney disease in African-descent individuals. A better understanding of the disease mechanisms responsible for glomerular injury in autosomal dominant MYH9 syndromes will lead to fuller appreciation of the role of this gene in glomerular biology.

A new mutation of MYH9 gene in a May-Hegglin anomaly family

Objective To identify a MYH9 gene mutation in a May-Hegglin abnormal family in China.Methods Clinical information and laboratory data of a family of MHA was collected.Cytomorphologic examination of peripheral blood and bone marrow smears were performed with Wright-Giemsa stain.The liver function tests,renal function tests,clot retraction time,platelet function tests and coagulation function tests were performed.The sequences of exons 1,10,25,26,30,38,39 and 40 in the MYH9 gene of the two patients and the normal controls were amplified with PCR.and the PCR products were sequenced.Results The proband and his affected mother manifested a typical triad of thrombocytopenia,giant platelets,and inclusion bodies in leukocytes.while their test results of liver function,renal function,clot retraction time,platelet function and coagulation function test were normal.A 4270G→A mutation(GAG→AAG)in the exon 30 of the MYH9 gene existed in the proband and his affected mother,while the same mutation in normal controls could not be found.Conclusions The cases of May-Heggelin anomaly showed typical triad of thrombocytopenia,giant platelets,and inclusion bodies in leukocytes.Mutation of the MYH9 gene exists in exon 30(Asp1424Asn)in this family and the new point mutation was first reported in China. Key words: May-Hegglin Anomaly; Hereditary diseases; Phenotype; Myosin heavy chains; Mutation

The May-Hegglin anomaly in a kidney transplant recipient.

We report a 37-year-old renal transplanted patient with thrombocytopaenia. He had May–Hegglin anomaly (MHA) inherited from his father, who died due to myocardial infarction subsequent to two renal transplantations. At the age of 15 years, proteinuria was found, but he was not biopsied. In 1982, he underwent splenectomy because of trauma. In 1989, when he was 17, renal function was found to be decreased. Five years later, he started haemodialysis and at 24 years he underwent live related kidney transplantation. Serum creatinine was always found stable around 1.9 mg/dl on cyclosporine, azathioprine and steroids. Automated blood count reported a number of platelets around 8000/μl with a mean volume of 20.3 fl (normal range 7.2– 11.1 fl). However, blood cell counters have a defined volume window for platelet counting and large macrothrombocytes are classified as red blood cells, meaning that platelet number is underestimated (Figure 1). The true value of platelets after count with the microscope was around 30 000/μl. He was completely asymptomatic, without any bleeding tendency. MHA is a rare autosomal dominant platelet disorder, characterized by macrothrombocytopaenia and granulocyte inclusion bodies. The mutation involves the MYH9 gene, localized in chromosome 22q, which encodes a heavy chain of non-muscle myosin IIA. MYH9-related hereditary macrothrombocytopaenia disorders include: MHA, Ebstein, Fechtner and Sebastian syndromes, which are characterized by nephritis, hearing loss and cataract [1]. In 1992, Nel et al. [2] reported two cases of MHA incidentally discovered in a patient and his brother during investigation for end-stage renal failure and workup for renal transplantation. Alhindawi and Al-Jbour [3] described an association between Epstein syndrome and chronic nephropathy. Recently, Singh et al. [4] suggested that MYH9 gene alterations are associated with a greater risk of focal segmental glomerulosclerosis and hypertensive nephrosclerosis in African Americans.

Anesthetic Management of 7 Deliveries in 3 Sisters With the May-Hegglin Anomaly

Anesthetic Management of 7 Deliveries in 3 Sisters With the May-Hegglin Anomaly

Anesthetic Management of Seven Deliveries in Three Sisters with the May-Hegglin Anomaly

May-Hegglin anomaly is a rare genetic hematological disorder characterized by thrombocytopenia, but platelet function is usually normal. Three sisters with May-Hegglin anomaly and thrombocytopenia (platelet counts 14,000-100,000/mm(3)) were given neuraxial anesthesia for a total of 7 deliveries, 5 vaginal and 2 cesarean. None of the women had complications and no blood products were transfused.

Clinical manifestation and molecular genetic characterization of MYH9 disorders

Currently, the May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FTNS) and Epstein (EPS) syndrome are considered to be distinct clinical manifestations of a single disease caused by mutations of the MYH9 gene encoding the heavy chain of non-muscle myosin IIA (NMMHC-IIA). Manifestations of these disorders include giant platelets, thrombocytopenia and combinations of the presence of granulocyte inclusions, deafness, cataracts and renal failure. We examined 15 patients from 10 unrelated families on whom we performed immunostaining of NMMHC-IIA in blood samples. Polymerase chain reaction (PCR) analysis of selected exons of the MYH9 gene revealed mutations in nine samples with one novel mutation. Results of fluorescence and mutational analysis were compared with clinical manifestations of the MYH9 disorder. We also determined the number of glycoprotein sites on the surface of platelets. Most patients had an increased number of glycoproteins, which could be due to platelet size.

Renin-angiotensin system blockade is effective in reducing proteinuria of patients with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome)

Fetchner syndrome (FTNS, OMIM 153640) is an autosomal dominant disorder characterized by the association of macrothrombocytopaenia, leukocyte inclusions, sensorineural deafness, cataracts and nephropathy often leading to end-stage renal disease (ESRD) [1]. Epstein syndrome (EPTS, OMIM 153650) presents the same features of FTNS, with the exception of leukocyte inclusions and cataracts [2]. Recently, it was shown that both FTNS and EPTS derive from mutations of MYH9, the gene for the heavy chain of non-muscle myosin IIA [3,4]. The same gene was found to be also responsible for two non-syndromic forms of inherited macrothrombocytopaenia with leukocyte inclusions, May-Hegglin anomaly (MHA, OMIM 155100) and Sebastian syndrome (SBS, OMIM 605249) [3]. Further studies demonstrated that patients initially diagnosed as having MHA/SBS can subsequently develop nephropathy, deafness and/or cataracts, while affected relatives of FTNS or EPTS patients present for all their lifetime a clinical picture indistinguishable from that of MHA/SBS subjects [5]. Moreover, immunofluorescence studies showed that leukocyte inclusions containing the MYH9 protein are present not only in MHA/SBS and FTNS, but also in all patients with EPTS [5]. Therefore, it was clear that FTNS, EPTS, MHA and SBS are not distinct entities, but rather they represent different clinical presentations of a single disease, characterized by the constant finding of congenital thrombocytopaenia and leukocyte inclusions, and possible development of nephropathy, deafness and/or cataracts in

High-resolution melting analysis for detection of MYH9 mutations

May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FTNS) and Epstein (EPS) syndromes are rare autosomal dominant disorders with giant platelets and thrombocytopenia. Other manifestations of these disorders are combinations of the presence of granulocyte inclusions and deafness, cataracts and renal failure. Currently, MHA, SBS, FTNS and EPS are considered to be distinct clinical manifestation of a single illness caused by mutations of the MYH9 gene encoding the heavy chain of non-muscle myosin IIA (NMMHC-IIA). As the MYH9 gene has a high number of exons, it takes much time and material to use this method for the detection of MYH9 mutations. Recently, a new method has been introduced for scanning DNA mutations without the need for direct sequencing: high-resolution melting analysis (HRMA). Mutation detection with HRMA relies on the intercalation of the specific dye (LC Green plus) in double-strand DNA and fluorescence monitoring of PCR product melting profiles. In our study, we optimized the conditions and used HRMA for rapid screening of mutations in all MYH9 exons in seven affected individuals from four unrelated families with suspected MYH9 disorders. Samples identified by HRMA as positive for the mutation were analysed by direct sequencing. HRMA saved us over 85% of redundant sequencing.

Usefulness of immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A for diagnosing in two sisters with May-Hegglin anomaly

Usefulness of immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A for diagnosing in two sisters with May-Hegglin anomaly

The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway

The gene implicated in the May-Hegglin anomaly and related macrothrombocytopenias, MYH9, encodes myosin-IIA, a protein that enables morphogenesis in diverse cell types. Defective myosin-IIA complexes are presumed to perturb megakaryocyte (MK) differentiation or generation of proplatelets. We observed that Myh9(-/-) mouse embryonic stem (ES) cells differentiate into MKs that are fully capable of proplatelet formation (PPF). In contrast, elevation of myosin-IIA activity, by exogenous expression or by mimicking constitutive phosphorylation of its regulatory myosin light chain (MLC), significantly attenuates PPF. This effect occurs only in the presence of myosin-IIA and implies that myosin-IIA influences thrombopoiesis negatively. MLC phosphorylation in MKs is regulated by Rho-associated kinase (ROCK), and consistent with our model, ROCK inhibition enhances PPF. Conversely, expression of AV14, a constitutive form of the ROCK activator Rho, blocks PPF, and this effect is rescued by simultaneous expression of a dominant inhibitory MLC form. Hematopoietic transplantation studies in mice confirm that interference with the putative Rho-ROCK-myosin-IIA pathway selectively decreases the number of circulating platelets. Our studies unveil a key regulatory pathway for platelet biogenesis and hint at Sdf-1/CXCL12 as one possible extracellular mediator. The unexpected mechanism for Myh9-associated thrombocytopenia may lead to new molecular approaches to manipulate thrombopoiesis.

Assessment of MYH9-Related Syndromes among a Series of Patients with Constitutional Macrothrombocytopenia (MT).

MYH9-related disorders are autosomal dominant giant platelet syndromes with a wide phenotypic variability known under the following names: May Hegglin Anomaly (MHA), Fechtner Syndrome (FTNS), Epstein Syndrome (EPS), Sebastian Syndrome (SBS) and Alport-like Syndrome with MT. The aim of the study was to identify MYH9-related syndromes in a series of 43 propositi with constitutional MT. In this group, 26 have a characteristic MYH9-syndrome phenotype. The 17 other patients have a constitutional MT of uncertain etiology, 8 of them presenting a partial MYH9 syndrome phenotype. The leukocyte repartition of the Non-Muscle Myosin Heavy Chain IIa (NMMHC-IIA) encoded by the MYH9 gene was explored by May-Grunwald-Giemsa staining of blood smears or by immunofluorescence, while platelets were also examined by electron microscopy (EM). The MYH9 gene was studied by genomic DNA amplification and direct sequencing of the 8 exons in which mutations have been published (Dong, 2005). The results are the following: of the 17 patients with constitutional MT of unknown etiology, no MYH9 mutations were found; in contrast, 24/26 (92.3%) patients with a characteristic MYH9-syndrome phenotype were heterozygous for a MYH9 mutation. Among their 29 family members, 5 were heterozygous for the mutated allele. In 4 families, the mutations were found only in the propositus but not in the parents, suggesting that they might be either de novo mutations or the results of somatic mosaicism, as already published ( Kunishima et al, 2005). Six mutations are novel: F1446L, K1937X, A44P, D1424E in 4 MHA patients, W33C in 1 patient with MHA/SBS, and, interestingly, D1447V was associated with 2 different phenotypes, MHA and FTNS. As already published, the majority of the mutations in the C-terminus of the NMMHC-IIA are associated with a pure hematologic disorder. In contrast, the N-terminus mutations were more generally associated with a more severe phenotype with renal manifestations. However the same mutation can be associated with different phenotypes: S96L with FTNS, EPS and SBS/MHA, D1447V with MHA and FTNS. In addition the R702C mutation, which has been identifed in 2 cases with an identical FTNS phenotype, is associated with 2 different leukocyte NMMHC-IIA distributions. No MYH9 mutation could be detected in 2 patients with FTNS. These results, as a whole, are in agreement with the hypothesis that mutations in other genes than MYH9 might be involved in defining the phenotypes of such syndromes. The genotype of the 17 patients with uncertain etiology remains to be identified. The interest to diagnose MYH9 mutations is:to avoid misdiagnosis and inadequate therapy for patients with thrombocytopenia (2 patients initially diagnosed as ITP patients underwent splenectomy);to detect as early as possible the risk and occurrence of renal failure, deafness and cataracts (1 patient initially diagnosed as a SBS patient developed a renal failure characteristic of FTNS).A long-term follow-up of the patients with MYH9 mutations is of a high interest for a better knowledge of the relationship between the mutation and the phenotypic expression.

Identification of a novel MYH9 mutation in a patient with May‐Hegglin anomaly

Identification of a novel <i>MYH9</i> mutation in a patient with May‐Hegglin anomaly

Genotype–phenotype correlation in MYH9‐related thrombocytopenia

Mutation of the non-muscle myosin heavy chain type II-A results in MYH9-related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high-performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9-related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C-terminal coiled coil region or truncation of the tailpiece is associated with haematological-only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non-haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype-phenotype relationship.

Perioperative management of a patient with May-Hegglin anomaly requiring craniotomy

May-Hegglin anomaly (MHA) is a rare type of autosomal dominant platelet disorder associated with mutations in the gene encoding nonmuscle myosin heavy chain 9 (MYH9). It is characterized by the presence of large platelets, leukocyte inclusions, and thrombocytopenia. The bleeding tendency is usually mild, but severe hemorrhages have been reported. This is the first reported case of a patient with MHA who underwent craniotomy for intractable seizure disorder of temporal lobe origin. Patients who have thrombocytopenia have a higher likelihood of developing intraoperative or postoperative intracranial hematoma and bleeding complications. The patient was administered desmopressin (DDAVP) prior to the neurosurgical procedure and had no complications. With this approach, the use of platelet concentrates could be avoided. We discuss the role of DDAVP in MHA and related platelet disorders and review the current literature.

A Novel Frameshift Mutation in a Case of Familial May-Hegglin Anomaly.

The May-Hegglin anomaly is a rare, autosomal dominant condition that is characterised by thrombocytopaenia, anisocytosis, and Dohlë-like inclusion bodies in leukocytes. The disorder generally results in a mild bleeding tendency. May-Hegglin anomaly results from defects in the MYH9 gene, which encodes the heavy chain of nonmuscle myosin IIA. The gene maps to chromosome 22q12.3-q13.2, comprises 40 exons, and produces a 5.8kb mRNA transcript.We present a case of familial May-Hegglin anomaly. This kindred was first identified, and published, in 1964; but no further analyses were carried out until recently.The proband, now aged 80 years, has a life long history of easy bruising and epistaxis, although the symptoms have improved with increasing age. Her sister (deceased) and daughter reported similar symptoms: the daughter requiring splenectomy for thrombocytopaenia at age 9 years. The proband has also suffered from deafness for in excess of 60 years.Recent investigations of the proband revealed a mild thrombocytopaenia, and the characteristic blood film of May -Hegglin anomaly. Platelet and neutrophil morphology were also consistent with the disorder. Karyotype analysis revealed good quality G banding throughout chromosome 22, and no gross alteration in the region 22q11.2., 22q13. Direct sequencing of the MYH9 gene identified a heterozygous deletion of a single base in a run of Gs at nucleotide positions 5818–5821 (codons 1940–1941). This frame shift mutation leads to the creation of a premature termination sequence at codon 1947, and the loss of the last fourteen amino acids. The deletion introduces a restriction site, and endonuclease digestion of a panel of normals failed to detect this change. Together with the fact that this is a conserved region across species (human, rat, rabbit, chicken), it is probable that this deletion is the causative mutation in this kindred.This novel mutation represents the second reported defect affecting the tail-piece domain in May-Hegglin anomaly. The protein's two heavy chains homodimerise in this region to form a tail, and multiple polypeptides associate through this tail domain to form bipolar filaments. Therefore, a mutation in this domain may exert its effect by the inhibition of myosin filament assembly.To date, approximately 20 different mutations have been described in the MYH9 gene giving rise to not only May-Hegglin anomaly, but also the similar disorders of Fechtner syndrome, Sebastian syndrome and Epstein syndrome. In fact some mutations have been identified in patients with different diagnoses. The proband presented here has a long standing diagnosis of May-Hegglin anomaly, but does exhibit one symptom (deafness) more usually associated with Fechtner syndrome. The genetic, phenotypic and clinical overlap in these disorders suggest that these actually represent allelic variations of a single genetic disorder, which should more correctly be termed ‘MYHIIA syndrome'.